The present invention relates to the preparation of beta-ketoesters useful in preparing quinolone antibiotics.
European Patent Application Publication Number 0215650 discloses quinolone antibiotics, including 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(1S:4S)-5-methyl-2,5-diazabicyclo-[2. 2.1]hept-2-yl-4-oxo-3-quinoline-carboxylic acid (danofloxacin), a quinolone being developed for animal health use, and 1-cyclopropyl-6-fluoro-1,4-dihydro-7(1S:4S)-8-methyl-3,8-diazabicyclo-[3.2 .1]oct-3-yl-4-oxo-3-quinoline-carboxylic acid,
International Application No. PCT/US89/03489, filed Aug. 16, 1989, discloses 7-azabicyclo-substituted quinolone carboxylic acids having antibacterial activity.
European Patent Application 89304697.9 discloses compounds of the formula ##STR5## wherein R is C.sub.1 -C.sub.4 alkyl and X is fluoro, chloro or bromo as intermediates for preparing quinolone antibiotics. The compounds are prepared by reacting 2-halo-4,5-difluoro-acetophenone, wherein halo is fluoro, chloro or bromo, with a strong base and then reacting the resulting anion with a C.sub.1 -C.sub.4 alkyl cyanoformate. Alternatively, 2-halo-4,5-difluorobenzoyl chloride, wherein halo is fluoro, chloro or bromo, is reacted with the dilithium salt of a mono (C.sub.1 -C.sub.4) alkyl malonate.
P. Poller and S. Gelen, Synthesis, 142-143 (1978) refer to the reaction of monoethyl malonate with isopropyl magnesium bromide followed by addition of an acid chloride of the formula ##STR6## to give a beta-keto ester. Pollet and Gelen used acid chlorides wherein R.sup.1 was hydrogen or methyl; R.sup.2 was hydrogen, methyl or --COOC.sub.2 H.sub.5 ; and R.sup.3 was hydrogen or methyl.
D. W. Brooks et al. Angew. Chem. Int. Ed. Engl., 18, 72-74 (1979) refer to the reaction ##STR7## wherein R.sup.1 is selected from phenyl, phenylethyl, and a variety of saturated and unsaturated straight chain hydrocarbon groups, and R.sup.2 is hydrogen or methyl.
T. N. Salzmann et al., J. Am. Chem. Soc., 102, 6161-6163 (1980), refer to the reaction of a compound of the formula ##STR8## wherein R is imidazolyl with the magnesium salt of the mono para-nitrobenzyl ester of malonic acid in tetrahydrofuran at room temperature to provide a betaketoester.
M. W. Rathke and P. J. Cowan, J. Org. Chem., 50, 2622-2624 (1985) refer to C-acylation of diethyl malonate with acid chlorides in the presence of magnesium chloride and pyridine or triethylamine.
J. Wemple, 1989 International Chemical Congress of Pacific Basic Societies, refers to the following reaction for use in preparing 6-fluoroquinoline antibacterial agents: ##STR9## wherein Ar phenyl; 3,4-dichlorophenyl; 2,4,5-trifluoro-3-chlorophenyl; pentafluorophenyl; 2,3,4,5-tetrafluoro-6-nitrophenyl; or p-methoxyphenyl.